Dehydrogenative α-oxygenation of ethers with an iron catalyst

Article abstract of DOI:10.1021/ja502167h

Selective α-oxidation of ethers under aerobic conditions is a long-pursued transformation; however, a green and efficient catalytic version of this reaction remains challenging. Herein, we report a new family of iron catalysts capable of promoting chemoselective α-oxidation of a range of ethers with excellent mass balance and high turnover numbers under 1 atm of O₂ with no need for any additives. Unlike metalloenzymes and related biomimetics, the catalyst produces H₂ as the only byproduct. Mechanistic investigations provide evidence for an unexpected two-step reaction pathway, which involves dehydrogenative incorporation of O₂ into the ether to give a peroxobisether intermediate followed by cleavage of the peroxy bond to form two ester molecules, releasing stoichiometric H₂ gas in each step. The operational simplicity and environmental friendliness of this methodology affords a useful alternative for performing oxidation, while the unique ability of the catalyst in oxygenating a substrate via dehydrogenation points to a new direction for understanding metalloenzymes and designing new biomimetic catalysts.

Full text of DOI:10.1021/ja502167h

Article
pubs.acs.org/JACS
Dehydrogenative α‑Oxygenation of Ethers with an Iron Catalyst
Angela Gonzalez-de-Castro, Craig M. Robertson, and Jianliang Xiao*
Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, United Kingdom
S
* Supporting Information
ABSTRACT: Selective α-oxidation of ethers under aerobic conditions is a long-
pursued transformation; however, a green and efficient catalytic version of this
reaction remains challenging. Herein, we report a new family of iron catalysts
capable of promoting chemoselective α-oxidation of a range of ethers with excellent
mass balance and high turnover numbers under 1 atm of O2 with no need for any
additives. Unlike metalloenzymes and related biomimetics, the catalyst produces H2
as the only byproduct. Mechanistic investigations provide evidence for an
unexpected two-step reaction pathway, which involves dehydrogenative incorpo-
ration of O2 into the ether to give a peroxobisether intermediate followed by
cleavage of the peroxy bond to form two ester molecules, releasing stoichiometric
H2 gas in each step. The operational simplicity and environmental friendliness of
this methodology affords a useful alternative for performing oxidation, while the
unique ability of the catalyst in oxygenating a substrate via dehydrogenation points
to a new direction for understanding metalloenzymes and designing new biomimetic catalysts.
INTRODUCTION
■
Catalytic selective oxidation of organic chemicals is identified as
the most important area to impact the future chemical
industry.1 Nature has mastered the art of oxidation using
metalloenzymes, which are capable of selectively oxidizing
various substrates with O2 under mild conditions. Depending
on the oxygenases used, different modes of O2 activation are
possible, leading to the insertion of one or both oxygen atoms
of O2 into a C−H bond (Figure 1). For instance, mono-
oxygenases operate by inducing the cleavage of the O−O bond
at the metal center to form a highly electrophilic iron-oxo
species, through which an alkane can be oxidized into an
alcohol, releasing water as the byproduct.2 Inspired by nature, a
great variety of iron and copper-based biomimetic catalysts
have been designed to replicate and expand naturally occurring
oxidations.3 However, these biomimetic catalysts generally
require the use of more expensive H2O2 as oxidant to generate
the high valent FeIVO or FeVO(OH) species.3
Although dioxygen is the most desired oxidant in oxidation
chemistry,1−4 its activation for catalytic oxidations by synthetic
iron complexes has proven a significant challenge. Only a few
examples have been reported so far, and they usually rely on the
use of additives.5,6 For instance, the Gif-type systems7 and
Figure 1. Modes of selective oxidation of organic substrates.
macrocyclic FeII complexes8 can catalyze the oxidation of
alkanes in the presence of a reductant, while some FeIII salts9
and biomimetic FeIII complexes10 selectively mono-oxidize
organic substrates with the aid of a sacrificial substrate.
Photoassisted activation of dioxygen has also been explored.11
Thus, the design of well-defined iron complexes as potential
catalysts for selective oxidation using O2 under additive-free
conditions remains challenging. This is particularly the case for
substrates bearing electron-rich functionalities,12 such as ethers,
where poor chemoselectivity,13−17 poor substrate scope,3c,16−22
and harsh oxidizing conditions13,15,18 are usually encountered.
α-Oxidation of ethers to esters is an attractive transformation,
due to their applications in the synthesis of complex natural
Received: March 6, 2014
Published: May 16, 2014
© 2014 American Chemical Society
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products and biologically active molecules.23 Stoichiometric
amounts of metal oxides, such as RuO4,13 CrO3,18 and
permanganates,24 were early attempted for this transformation.
More modern methodologies are based on catalytic metal
complexes of Ru14 and Au,15 using stoichiometric strong
oxidants. Greener aerobic oxidation has been attempted with
catalysts based on Ir,19 Rh,20 Pt,21 Co,22 and Cu complexes;16
however, they all display limited efficiencies, poor mass balance,
limited scope, and poor functional group tolerance, while
requiring additives (Figure 2A). Surprisingly somehow, the use
RESULTS AND DISCUSSION
■
1. Synthesis of PyBisulidine Ligands. The application of
tetradentate N-donor ligands for biomimetic oxidations has
been extensively studied either as porphyrin type skeletons or
as nonhaem designs.3 However, tridentate N-donor ligands are
less explored, and their application is surprisingly limited
mainly to olefin epoxidation.26 Recently, a novel pyridine
bisimidazoline (PyBidine) ligand was reported and exploited in
Cu-catalyzed [3+2] cycloadditions27 and Mannich reactions.28
Inspired by the bulky, flexible PyBidine skeleton and the
influence of electron-withdrawing groups of ligands on iron-
catalyzed oxidation,29 we hypothesized that sulfonylation of the
PyBidine moieties could give rise to a new family of ligands
with interesting coordinating properties, which might confer
facilely tunable Lewis acidity onto or steric hindrance around
the iron, enhance the ability of iron for O2 activation, and allow
for better catalytic activity and selectivity.
An ample variety of sulfonylated PyBidine ligands,
PyBisulidines, were synthesized with excellent yields by simple
condensation of pyridine-2,6-dicarboxaldehyde with sulfonyl
diamine derivatives under catalytic acidic conditions (eq 1).
Reacting L1 with Fe(OTf)2 in THF led to a THF-ligated
complex [FeL1(THF)(OTf)2], the structure of which has been
determined by X-ray diffraction (Figure 3). The complex shows
a distorted octahedral geometry with two axial OTf ligands and
an equatorial THF. Although surrounded by the sterically
demanding L1, the Fe−O3 distance of 2.042 Å is considerably
shorter than those found in the iron porphyrin [Fe(TPP)-
(THF)2]-type complexes and other iron−THF species,30,31
suggesting a highly electrophilic FeII center.
2. Fe(OTf)2−L1-Catalyzed Aerobic Oxidation of THF
Substrates. When investigating possible catalytic reactions
with the complex synthesized, small amounts of γ-butyrolac-
tone were detected in the bright orange THF solution of
[FeL1(THF)(OTf)2]. Prompted by this observation, we set
out to explore this complex as a potential catalyst for aerobic
oxidation of THF. Exposing a stirred THF solution of the
complex to 1 atm of O2 indeed led to the isolation of γ-
butyrolactone, with a TON of 98 in 24 h at 40 °C. Subsequent
optimization of the reaction conditions with the in situ
prepared catalyst, which behaved similarly to [FeL1(THF)-
(OTf)2], raised the TON to 312 at 60 °C. The TON increased
to 412 in a prolonged time of 48 h (Table 1, entries 1,2).
Control experiments showed that no reaction occurred in the
absence of L1, Fe(OTf)2, or O2, showing that the three
components are indispensable for the oxidation (see the
Supporting Information).
Figure 2. Literature examples of ether oxidation.
of cheaper and environmentally friendly iron catalysts for the
oxidation of ethers is limited to the example of a FeCl2-
catalyzed oxidation of THF under CO2/O2 atmosphere, which
yields a variety of species (Figure 2B),17 and that of a
biomimetic (S,S)-Fe(PDP) catalyst, which oxidizes THF and
THP in preparative yields with H2O2/AcOH3c (Figure 2C).
Although a turnover number (TON) of 3 was initially achieved
with the latter due to the large amount of catalyst used (15 mol
%), higher efficiencies have been subsequently reported with
the Fe-(PDP) and structurally related biomimetic catalysts.25
Considering the limitations of the reported catalysts and the
appeal of an iron catalyst, we started a program to investigate
new ligand designs, aiming for more efficient iron-catalyzed
aerobic oxidations. Herein, we disclose a novel family of iron
catalysts bearing pyridine bissulfonylimidazolidine ligands, and
their application in the α-oxidation of ethers under 1 atm of O2
and additive-free-conditions with high chemoselectivity and
excellent mass balance. We also reveal that the oxidation
appears to proceed via an unprecedented dehydrogenative−
oxygenation mechanism, with H2 released as the sole byproduct
(Figure 1).
Further optimization revealed that modification of the ligand
structure resulted in the most significant oscillations in the
catalytic activity. The PyBisulidine ligands exhibited the highest
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benzyl group, afforded no activity at all (entry 7), indicating
that both electronic and steric effects are important factors in
modulating the catalyst activity. Using the conjugated L7 as
ligand, which bears no NH proton, resulted in a significant
TON reduction and lower selectivity; the undesired autox-
idation product tetrahydrofuran α-hydroperoxide was observed
as the major product (entry 8). Additionally, replacement of L1
with the previously reported PyBidine ligand L8 significantly
lowered the catalytic activity, showing the beneficial effect of
the sulfonyl group (entry 9). Still further, the asymmetric ligand
L9 and bidentate ligands L10−L12 were all found inactive
(entries 10−13). Finally, the Fe(OTf)2−L1-catalyzed aerobic
oxidation of THF was found compatible with arene solvents,
whereas halogenated or donor solvents were found very
detrimental for the catalyst activity (see the Supporting
Information).
Figure 3. Formation of the THF-ligated [FeL1(THF)(OTf)2]
complex, and its X-ray structure. Selected interatomic distances [Å]
and angles [deg]: Fe1−O3 2.042(3), Fe1−O5 2.157(2), Fe1−N4
2.117(3), Fe1−N14 2.252(2), N14−Fe1−N14 151.24(12), N4−Fe1−
N14 75.62(6), O3−Fe1−N14 104.38(6), O3−Fe1−O5 88.73(6).
Table 1. Effect of Ligands on the Iron-Catalyzed Aerobic α-
a
Oxidation of THF
b
entry
1
ligand
butyrolactone/TON
L1
312
412
283
207
194
121
NR
20
c
2
L1
Although the conversion of the aerobic oxidation of 1a was
low, it should be noted that 2.3 mmol of γ-butyrolactone was
isolated from a one-step reaction (Table 2, entry 1). Moreover,
α-substituted γ-butyrolactones were also obtained from THF-
type substrates with good chemoselectivity, mass balance, and
functional group tolerance (Table 2; also see below). In
addition, the oxidation with Fe(OTf)2−L1 is easy to conduct,
with the starting substrate and the lactone product being easily
separable, and it may still be possible to increase the conversion
further (see below). The resulting substituted γ-butyrolactones
are widely used in synthetic chemistry32 and are common
motifs in pharmaceutical33 and natural23c,34 products, and
biomass processing.35 To the best of our knowledge, this is the
first catalyst in the literature that allows access to such
functionalized compounds via aerobic oxidation. An exception
is seen in 2b, which can be obtained via a rhodium catalyzed
oxidation, albeit with lower efficiency, harsher conditions, and
longer reaction times (TON of 150 in a 7 day reaction under
CO2/O2 pressure).20
3
4
5
6
7
L2
L3
L4
L5
L6
d
8
L7
9
10
11
12
13
L8
50
L9
NR
NR
NR
NR
L10
L11
L12
a
Reaction conditions: distilled THF (2.0 mL), in situ prepared
Fe(OTf)2−ligand complex (5.65 × 10−3 mmol, 0.02 mol %), O2 (1
b
atm) at 60 °C, 24 h. TON refers to mmol of product per mmol of
c
d
catalyst. Reaction run for 48 h. Tetrahydrofuran hydroperoxide was
obtained as the major product, with peroxide/lactone = 4/1.
efficiency, especially when electron-donating groups were
present in the sulfonyl moiety (Table 1, entries 1−6).
Nonetheless, replacement of L1 with the more electron-rich
but much more sterically demanding L5 resulted in a 2.5-fold
reduction in the TON (Table 1, entry 6), and the sterically very
congested L6, in which the NH proton is replaced with a
3. Oxidation of Isochromans. To evaluate the applic-
ability of the Fe(OTf)2−L1-catalyzed oxidation of ethers, we
next investigated the α-oxidation of substituted isochromans.
The resulting products, isochromanones, are common motifs in
natural products and bioactive molecules.23b,36 To our delight,
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Table 2. Fe(OTf)2−L1-Catalyzed Aerobic Oxidation of THF
Table 3. Fe(OTf)2−L1-Catalyzed Aerobic Oxidation of
a
a
Substrates
Isochromans
a
Reaction conditions: substrate (2.0 mL), Fe(OTf)2 (2.0 mg, 5.65 ×
10−3 mmol), L1 (5 mg, 5.65 × 10−3 mmol), O2 (1 atm) at 60 °C, 48 h.
b
c
rsm: recovered starting material (unoxidized). TON refers to mmol
of isolated product per mmol of catalyst.
a
Reaction conditions: substrate (2.0 mL), Fe(OTf)2 (5.65 × 10−3
isochroman was oxidized with a 40% total yield, affording
isochromanone with a TON of 844 in an overnight reaction
(Table 3, entry 1). Isochroman-1-ol was not detected under
this reaction condition; however, the unusual ether byproduct 5
was generated in low yield (also see below). The catalyst
operates with high chemoselectivity even in the presence of
tertiary benzyl or O-alkyl substituents with no sign of tertiary
alcohol byproduct formation (entries 1−3). This selectivity is
further manifested when 3a was reacted for 5 days under the
same conditions, which afforded 4a and 5a in about the same
isolated yields with no overoxidation being observed (see the
Supporting Information). The reactions also proceeded with
excellent mass balance with no substrate decomposition, and
the unreacted starting material was easily recovered.
Although the presence of substituents in the alkyl ring barely
affects the reaction yields, substitution in the aromatic ring
revealed a dramatic electronic effect, with electron-withdrawing
groups inducing higher TONs and electron-donating groups
exerting the opposite effect (entries 4−8). In particular, the
trifluoromethyl- and fluorine-substituted 4d and 4e were
isolated in over 1000 TON (6.63 and 7.09 mmol isolated,
respectively). This appears to suggest the involvement of
proton transfer in the turnover limiting step.
b
mmol), L1 (5.65 × 10−3 mmol), O2 (1 atm) at 60 °C, 16 h. rsm:
recovered starting material (unoxidized). Isolated yield of both
oxidized products. TON refers to mmol of isolated product per mmol
of catalyst. Isolated yield of the individual product. Substrate (1.5 g)
was added to a C6H6 (0.5 mL) solution of in situ formed Fe(OTf)2−
L1 (0.02 mol %) by heating at 35 °C for 1 h.
c
d
e
f
mmol) in a single-step reaction (Table 4, entry 4), indicating
the potential applicability of our catalyst in natural product
synthesis. Additionally, the scope of the reaction can be
extended to a thiophene derivative, although the yield was low
(Table 4, entry 2). To the best of our knowledge, this is the first
iron catalyst capable of selectively oxidizing such electron-rich
substrates to isochromanones.
Although biomimetic iron complexes catalyze the oxidation
of ethers with H2O2 under acidic conditions, electron-rich aryl
alkanes are decomposed.3c,12 Among stoichiometric oxidants,
ceric ammonium nitrate (CAN) oxidizes electron-rich isochro-
mans under mild conditions, albeit with poor chemo-
selectivity.38 SeO2 can oxidize electron-rich isochromans in
low yields through tedious procedures that require harsh
reaction conditions.39 Toxic CrO3 can be used under milder
conditions;39 however, the reactions are substrate dependent.18
Indeed, when the substrate 3l was treated with a stoichiometric
amount of CrO3, the quinone product 3m was obtained
predominantly, with only traces of the desired isochromanone
4l obtained (eq 2). Oxidation of p-dimethoxybenzene moieties
Very electron-rich isochromans can also be oxidized (Table
4). Although the TONs were reduced, very good mass balance
was again demonstrated, allowing for full recovery of the
unreacted starting material. Thus, the protected form of the
natural product aurocitrine37 was isolated in 5% yield (0.36
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Table 4. Fe(OTf)2−L1-Catalyzed Aerobic Oxidation of
Table 5. Fe(OTf)2−L1-Catalyzed Regioselective Aerobic
a
a
Electron-Rich Isochromans
Oxidation of Phthalans
a
Reaction conditions: substrate (2.0 mL), Fe(OTf)2 (5.65 × 10−3
b
mmol), L1 (5.65 × 10−3 mmol), O2 (1 atm) at 60 °C, 16 h. rsm:
recovered starting material (unoxidized). TON refers to mmol of
isolated product per mmol of catalyst. Substrate (1.5 g) was added to
c
d
a C6H6 (0.5 mL) solution of in situ formed Fe(OTf)2−L1 (0.02 mol
a
Reaction conditions: substrate (2.0 mL), Fe(OTf)2 (5.65 × 10−3
%) by heating at 35 °C for 1 h.
b
mmol), L1 (5.65 × 10−3 mmol), O2 (1 atm) at 60 °C, 16 h. rsm:
recovered starting material (unoxidized). TON refers to mmol of
isolated product per mmol of catalyst.
c
to quinones is often encountered when using stoichiometric
oxidants, such as CAN,40 MnO2,41 or hypervalent iodine.42
TON observed for 6e than 6f is consistent with a stronger
inductive effect by the nitrogen on the ortho methylene. In the
case of the heavier halogens, their significantly stronger para
directing effect (σm = 0.37 for Cl and 0.39 for Br vs σp = 0.23
for both) and larger size might result in the observed para
oxidation (Table 5, entries 2,3). These results, together with
those above, demonstrate that the Fe(OTf)2−L1-catalyzed
aerobic oxidation of ethers allows for the production of valuable
lactone products at the gram scale under green, mild, and
operationally simple conditions, thus addressing to a certain
degree the challenges facing the design of chemoselective and
stable homogeneous iron catalysts for selective oxidation on a
commercial scale.1,3a,48
5. Product Inhibition and Catalyst Reuse. While
Fe(OTf)2−L1 showed high chemoselectivity and TONs, the
oxidations above generally displayed relatively low conversions.
In an attempt to increase the efficiency of the Fe(OTf)2−L1-
catalyzed aerobic oxidations, higher catalyst loadings were
tested. However, no significant improvement was observed in
the oxidation of 1a or 3a when the catalyst loading was
increased under otherwise the same conditions (see the
Supporting Information). Further experiments revealed,
surprisingly somehow, that the loss of catalytic activity at a
4. Oxidation of Phthalans. Having showed the viability of
the catalyst in oxidizing isochromans, we turned the attention
to the oxidation of phthalans to phthalides, important building
blocks for more complex chemicals, such as dyes,43 natural
oils,44 fungicides,45 and biologically active compounds46 (Table
5). A similar strong electronic effect was observed for these
substrates, with higher yields obtained for substrates containing
electron-withdrawing groups. Interestingly, this electronic effect
can now be harnessed to direct the regioselectivity of the
oxidation. Thus, with a strong meta directing effect (σm = 0.34
vs σp = 0.06), the fluorine substitute induced exclusive
oxidation of the meta methylene unit to afford the ester 7a in
60% isolated yield and 1533 TON. Similarly, dihydrofuro[3,4]-
pyridines were regioselectively oxidized at the ortho or meta
position, leading to azaphthalide skeletons of pharmaceutical
and other industrial interest (Table 5, entries 5,6).47 The higher
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certain level of conversion results from product inhibition,
rather than catalyst decomposition. Thus, in the presence of the
ester product 4a (30%, chosen according to the yield obtained
under the normal conditions; see Table 3, entry 1), the
Fe(OTf)2−L1-catalyzed oxidation of 3a afforded only 6% of
additional 4a (eq 3), in stark contrast with the isolated yield of
TEMPO, or para-benzoquinone.49 Addition of any of these
reagents inhibited the formation of both isochromanone and
1,1′-oxidiisochroman with the former being more adversely
affected (Figure 4A). However, no adducts resulting from the
4a shown in Table 3. The oxidation was also inhibited by the
ether byproduct 5a (eq 4). Most likely, the inhibition arises
from the carbonyl coordination in the case of 4a, or the ether
chelation in the case of 5a, to the iron center, preventing the
coordination of 3a and hence its oxidation. This is in line with
the detrimental effect exerted by coordinating solvents
mentioned above.
Realizing the inhibition effect of product, it became possible
to increase the overall yield of the oxidation with Fe(OTf)2−
L1, particularly when the product could be readily separated
from the reaction mixture. This is demonstrated in the
oxidation of isochromans 3e and 3f (eq 5). After the initial
oxidation under the same conditions as those in Table 3, the
resulting solid products were removed, enabling the oxidation
to continue for another 16 h to give 4e and 4f in a total isolated
yield of 65% (1503 TON) and 59% (1282 TON), respectively,
with no product overoxidation (see the Supporting Informa-
tion). These results highlight the robustness of the iron catalyst
and point to a strategy for addressing the conversion issue in
question, that is, run the oxidation in a continuous flow reactor.
6. Mechanistic Investigations. Involvement of Radical
Species. The high chemoselectivity, unusual tolerance to
electron-rich groups, and strong electronic effect observed
suggest that the Fe(OTf)2−L1-catalyzed oxidation of ethers
may proceed by a mechanism different from the one involving
an electrophilic iron-oxo species or autoxidation mechanism.
Indeed, no alcohol products were detected even in conditions
of limited O2 in the reactions presented (see the Supporting
Information), which contrasts with the initial methylene
oxidation to alcohol and subsequent over-oxidation to its
ketone form observed in the methylene oxidation with H2O2
using the biomimetic Fe(PDP) catalyst.3c To gain insight into
these observations, preliminary mechanistic investigations were
performed. As such oxidation reactions often involve radical
intermediates, we first examined the Fe(OTf)2−L1-catalyzed
oxidation of ethers in the presence of a radical trapping reagent.
Isochroman was selected as a model substrate as no
uncontrolled autoxidation occurred upon addition of a radical
trapping agent, 2,6-ditbutyl-4-methylphenol (BHT), BrCCl3,
Figure 4. Experiments indicating no formation of freely diffusing
radicals during the oxidation.
substrate and the radical trap were observed, such as 1-
isochromanol or 1-bromoisochroman. Similarly, no products
commonly derived from radicals50 were observed when 3-
methyl-3,4-dihydro-1H-isochromene-5,8-dione was subjected
to the oxidation (Figure 4B).
To examine further the possible formation of radicals, the
aerobic oxidation of isochroman was conducted in the presence
of a radical initiator, benzoyl peroxide (Luperox),51 at 35 °C.
The presence of the initiator did not affect the oxidation of
isochroman to isochromanone (16% in its presence vs 17% in
its absence); however, a small amount of radical-derived
isochroman hydroperoxide 8 (ca. 2%) was detected (Figure
4C). Notably, the hydroperoxide product gained significance in
the absence of L1 and became the sole product when the
catalyst was omitted (see also the Supporting Information).
Formation of the oxidation dimer 5a was also observed in the
presence of the Fe(OTf)2−L1 catalyst (see also Table 3).
Although no clear evidence of the mechanism of its formation
has been obtained, it is likely that 5a is formed via a
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competitive, Fe(OTf)2−L1-catalyzed process. Its formation via
catalytic aerobic oxidation has not been reported; however,
exposure of 3a to stoichiometric52 or radical53 oxidants resulted
in the formation of 5a.
The ability of benzoyl peroxide to initiate radical reactions
with such ethereal substrates is also seen in the reaction of the
radical clock ( )-trans-(2-methoxymethyl)cyclopyl)benzene,54
which underwent rapid ring-opening when exposed to a small
amount of benzoyl peroxide under 1 atm of O2 (Figure 4D). In
sharp contrast, no reaction occurred when the radical initiator
was replaced with Fe(OTf)2−L1. The lack of reaction in the
case of the iron catalyst is probably due to the steric bulkiness
of the radical clock, which prevents its coordination to the iron
center (see the Supporting Information, where a sterically
demanding ether is shown to be equally inactive; also see
below). Taken together, these observations suggest that while
radicals may be generated in the Fe(OTf)2−L1-catalyzed
oxidation, freely diffusing carbon or oxygen-based radicals are
not involved.
Identification of a Peroxide Intermediate. Further probing
of the isochroman oxidation revealed a peroxy intermediate.
Thus, when the oxidation was stopped after 1 h reaction, 1,1′-
peroxydiisochroman 1255 was detected, apart from the expected
isochromanone 4a and the 1,1′-oxidiisochroman byproduct 5a
(Figure 5). Importantly, the peroxy species disappeared,
intact, establishing the intermediacy of the peroxide to
isochromanone. Apparently, the oxy species is not involved in
the formation of the ester product. To our surprise, this clean
transformation of 12 to 4a was also observed under a N2
atmosphere; however, no reaction occurred in the absence of
the iron catalyst. Interestingly, the reaction was not affected by
the addition of either an excess of a radical inhibitor para-
benzoquinone or the radical initiator benzoyl peroxide (see the
Supporting Information), indicating that no radical species are
involved at this stage of the isochroman oxidation. The
presence of isochroman did not affect this transformation either
(see the Supporting Information), nor was isochroman oxidized
under the N2 atmosphere, reinforcing that the oxidation of
isochroman to the peroxide 12 involves O2 while the
conversion of 12 to the ester does not.
Moreover, when the similar peroxide 13, which could be
isolated (see below), was subjected to a stoichiometric reaction
with Fe(OTf)2−L1, phthalide 7d was rapidly and exclusively
generated (eq 7), providing unequivocal evidence for the
intermediacy of the peroxide species in the Fe(OTf)2−L1-
catalyzed oxidation of ethers to lactones. To the best of our
knowledge, the catalytic conversion of a peroxide, such as 12, to
2 equiv of an ester like 4a is unprecedented. Mixtures of the
peroxide 12 and isochroman hydroperoxide 8 can be generated
from the autoxidation of 3a under prolonged aerobic exposition
(4 weeks)56 or pressurized O2 atmosphere (5 bar) for shorter
times (48 h).55
Evidence of H2 Gas Release. Further study into how the
oxidation proceeds revealed, much to our surprise, that the
oxidation is accompanied by release of H2, forming no H2O.
Thus, quantitative GC analysis established the stoichiometric
formation of H2 in the Fe(OTf)2−L1-catalyzed oxidation of
phthalan to phthalide, and showed that the H2 formation took
place in each individual step, that is, oxidation to afford the
peroxide and its subsequent conversion to phthalide (Figure 6).
Figure 5. Identification of a peroxide intermediate during the
oxidation of isochroman, and the X-ray structures of the peroxide
intermediate and the 1,1′-oxidiisochroman byproduct (cis and trans
refer to the positioning of the two ether oxygen atoms in 12).
1
In line with this observation, quantitative analysis with H
NMR showed that no water was formed in the oxidation of
phthalan to phthalide (see the Supporting Information).
Isolation of 13 was possible by running the catalytic oxidation
in a C6H6 solution and at lower temperature than in Table 3.
These results indicate that unlike common enzymatic
accompanied by an increase in the yield of 4a, following
further reacting overnight (see the Supporting Information). X-
ray crystallographic analysis of the isolated mixture confirmed
the structure of 1,1′-peroxydiisochroman 12 existing in two
conformational isomers and that of 1,1′-oxidiisochroman 5a
(Figure 5). These observations suggest that Fe(OTf)2−L1 is
capable of catalyzing rapid and selective formation of 1,1′-
peroxyisochroman, from which the isochromanone results.
To gain more evidence of the intermediacy of 12, an isolated
mixture of 12 and 5a (1.0:0.6 molar ratio) was exposed to a
1
catalytic amount of Fe(OTf)2−L1 at 45 °C (eq 6). Crude H
NMR spectra revealed a clean reaction in which the peroxide
12 was fully converted into 2 equiv of isochromanone 4a under
an O2 atmosphere, whereas 1,1′-oxidiisochroman 5a remained
Figure 6. H2 gas formation in the oxidation of phthalan.
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oxidations, the oxidation in question proceeds via an unusual,
sequential dehydrogenative oxygenation process. In fact, to the
best of our knowledge, there appears to be no literature report
of oxygenation coupled with dehydrogenation in enzymatic or
biomimetic catalysis.
Isotope Labeling. Still further, oxygen isotope labeling
experiments indicate that the initial formation of the peroxide
involves no cleavage of the O−O bond in O2. Thus, the
oxidation of phthalan to 1,1′-peroxybis(1,3-dihydroisobenzo-
furan) with a mixture of 18O2 and 16O2 afforded 16O−16O and
18O−18O containing peroxides; however, no crossover 16O−18O
peroxy species were detected in the MS analysis (eq 8). The
preservation of the O−O bond in the formation of the peroxide
suggests that an iron-oxo intermediate is not involved in the
oxidation mediated by Fe(OTf)2−L1.
To gain further insight into the conversion of the peroxide
intermediate to the ester product, a mixture of peroxides 13
and 14 was exposed to the Fe(OTf)2−L1 catalyst (Figure 7).
GC−MS monitoring of the reaction revealed the exclusive
formation of H2 and D2, suggesting that the cleavage of the
peroxide is likely to occur within the coordination sphere of the
iron center, involving no free alkoxide ion or free alkoxy radical
in the solution (see below).
Suggested Mechanism. The results above point to the
Fe(OTf)2−L1-catalyzed α-oxidation of ethers following an
unprecedented tandem dehydrogenative−oxygenation process
involving the formation of a peroxide intermediate, and the
peroxide cleavage appears to be the turnover-limiting step of
the catalytic process (Figure 8). Although the formation of the
Figure 8. Fe(OTf)2−L1-catalyzed α-oxidation of ethers via a tandem
dehydrogenative−oxygenation process.
The cleavage of the peroxide 13 to give off H2 (Figures 6 and
7) could involve a Fe−H hydride intermediate. Likewise, a Fe−
peroxide intermediate is unclear mechanistically, the preserva-
tion of the O−O bond in the peroxide intermediate and the
absence of water formation rule out the formation of an iron-
oxo species. Its formation via an autoxidation reaction is not in
agreement with the chemoselectivity observed and radical
trapping experiments either. Iron-induced CH activation of the
ethereal substrate followed by O2 attack appears also unlikely21
due to instability of metalated ethers and the easy formation of
cleavage products,58 which contradicts with the excellent mass
balance observed. Although CH activation of ethers via the
classic β-hydrogen (α to the oxygen) elimination following the
ether coordination to a metal is known,59 the ethers under the
conditions employed here undergo no hydrogen elimination or
exchange in the absence of O2, thus ruling out the possibility of
an anaerobic CH activation process initiated by iron. The
generation of oxonium ions from ethereal substrates under
catalytic conditions also seems improbable. These ions can be
easily trapped by nucleophiles;52a however, no lactol formation
was observed when the isochroman 3a was oxidized in the
presence of H2O or D2O.
Considering the coordination mode of [FeL1(THF)(OTf)2]
and particularly the short Fe−O3 (THF) distance (Figure 3),
we hypothesized that under the reaction conditions, the iron
complex may coordinate to one or two ethereal substrates.
Exposure to O2 atmosphere would easily result in the formation
of a FeIII superoxo species 16 in a fashion similar to that with
metalloenzymes3a and related biomimetics.60 The FeIII super-
oxo species could initiate the cleavage of the α-CH bond of the
Fe-bound ether substrate; hydrogen atom transfer to the FeIII
center followed by, or concurrent with, the attack of the
superoxo radical at the α carbon leads to a radical-ligated FeIII−
H hydride or a tight hydride−radical pair 17 (Figure 9). From
the species 17, a second hydrogen atom transfer and radical
combination afford 12 and a FeIV−(H)2 dihydride, which
undergoes reductive elimination to give off H2. This hypothetic
mechanism is consistent with the presence of radical species,
the high chemoselectivity of the oxidation, and the strong
electronic as well as steric bias manifested in the substrate
scope. Support for the mechanism is also found in the
Figure 7. Deuterium labeling experiments revealing no HD or D2
formation in the dehydrogenation of 13 in the presence of D2O, and
no HD formation in the reaction of a mixture of 13 and 14 (see the
Supporting Information for details).
D deuteride may form in the case of the deuterium-labeled
peroxide 14, which afforded D2. If so, it is likely that the iron
hydride may undergo H−D exchange with D2O. However, no
HD or D2 formation was observed when the oxidation of 13 to
7d was performed in the presence of D2O (Figure 7). We note
that no HD or D2 formation was reported either during the
dehydrogenative pyrolysis of hydroxyalkyl peroxides.57 The
reaction was proposed to occur via a radical-cage mechanism, in
which radical recombination is much faster than its
combination with solvent molecules.57
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Figure 9. Postulated formation of the peroxide intermediate.
literature. In particular, hydrogen transfer from a sp3 carbon α
to oxygen followed by the formation of FeIV−H hydride−
radical pair has been suggested for the coupling of alcohols with
alkenes.61 Many transition metals, including FeIV, are known to
form metal−dihydride and metal−dihydrogen complexes, from
which hydrogen release can occur.62
The cleavage of the peroxy bond to form the ester product
could proceed via the oxidative addition of the peroxide on the
Fe center followed by β-hydrogen abstraction, giving off H2
(Figure 10). It is known that some metal complexes can
Figure 11. Proposed catalytic cycle for the Fe(OTf)2−L1-catalyzed
aerobic oxidation of ethers to esters.
hydrogen abstraction sequence. The release of H2 is likely to be
a result of fast reductive elimination of hydrides at a FeIV center.
CONCLUSION
■
This Article reports a well-defined iron catalyst capable of
promoting selective oxidation of aromatic ethers to afford
valuable γ-butyrolactones, isochromanones, and phthalides
under 1 atm of O2 with high TONs, excellent mass balance,
and significantly improved functional group tolerance.
Although the conversions remain to be improved, considerable
amounts of product can be isolated in a one-step reaction, with
the substrates easily recovered. An unusual mechanism
involving dehydrogenation without initial metal-centered O−
O cleavage appears in operation, which may inspire new
thinking in understanding and mimicking iron-based mono and
dioxygenases. We note, however, that the details of the reaction
mechanism are yet to be delineated, in particular those
concerning the formation of the peroxide and its trans-
formation into the ester accompanied by H2 release.
Figure 10. Conversion of 12 to 4a via a hypothetic oxidative
addition−hydrogen abstraction sequence.
undergo oxidative addition of peroxides ROOR, resulting in
cleavage of the O−O bond.63 This cleavage may involve polar
addition of the RO−OR bond to a metal center generating a
M+−OR cation and a RO− anion, or concerted nonpolar
addition of the peroxide bond to give two M−OR bonds, or a
radical mechanism giving rise to a M•−OR and a RO•
radical.63a Because the oxidation with Fe(OTf)2−L1 leads to
no formation of HD (Figure 7), readily takes place in nonpolar
solvents such as benzene, and the catalytic conversion of 12 to
4a is insensitive to radical inhibitors, the oxidative addition of
the peroxide to the iron catalyst is likely to proceed via the
concerted pathway.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, and ligands and products character-
1
ization data including H and 13C NMR spectra and detailed
mechanistic data. This material is available free of charge via the
Internet at http://pubs.acs.org.
Bearing in mind the observations made with the isotope
labeling, the dehydrogenation step shown in Figure 10 may
involve consecutive β-hydrogen migration to the iron followed
by fast reductive elimination to release H2. Literature examples
are known of hydrogen abstract from iron-alkoxo species,
leading to dehydrogenation including release of H2, in catalysis
by both metal complexes and enzymes.64 In addition, under
pyrolytic conditions, hydroxyl65 and bis-hydroxyalkyl66 per-
oxides can give off hydrogen gas.
On the basis of these mechanistic investigations, a catalytic
cycle involving the inner-sphere formation of a peroxide
intermediate via the attack of an iron-superoxo radical at
coordinated ethers is postulated (Figure 11). Subsequent
conversion of the isolable peroxide intermediate to the ester
product may proceed through a concerted oxidative addition−
AUTHOR INFORMATION
Corresponding Author
jxiao@liv.ac.uk
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the EPSRC and University of Liverpool for
funding (AGdC) and to the EPSRC NMSSC at Swansea
University and the Analytical Services of the Department of
Chemistry at the University of Liverpool for product analysis.
We would like to express our deep gratitude to Dr. Sam Haq of
the Surface Science Research Centre of the University of
Liverpool for his assistance and advice in performing GC−MS
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